Antisense (AS) oligodeoxynucleotides (ODN) have been widely employed to perturb gene expression, and elucidate gene function in a laboratory setting. More recently my group, and others, have reported in vitro and in vovo models which demonstrate the potential therapeutic utility of AS ODN. Based on this body of work, we have instituted Phase I trials of AS ODN for the treatment of human leukemias at the Hospital of the University of Pennsylvania. While the results of these initial clinical trials may be viewed as encouraging, we appreciate that this approach to anti-cancer therapeutics can only be made practical if a more basic understanding of the "antisense mechanism" is developed. The long term goals of this project are to enrich our understanding of how AS ODN impair mRNA utilization in living cells, and to then use this knowledge in the development of ODN therapies for human leukemias. To study the mechanisms of ODN pertubation of gene function we will employ normal and neoplastic human hematopoietic cells as a model system. Specifically, we will examine how AS molecules impair the utilization of Vav mRNA in cells of this type. Vav protein is the product of a protooncogene which functions as an important signalling protein in hematopoietic cells. Our preliminary data, discussed below, suggests that Vav mRNA represents a rational therapeutic target in certain human leukemias. Accordingly, these studies will have both basic and translational relevance and will hopefully culminate in the institution of a Phase I clinical protocol for the treatment of human leukemia. Three specific aims have been developed to help us achieve this project's long term goals.